Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system

Karbian, Netanel, Eshed-Eisenbach, Yael, Zeibak, Marian, Tabib, Adi, Sukhanov, Natasha, Vainshtein, Anya, Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676, Fellig, Yakov, Peles, Elior and Mevorach, Dror 2023. Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system. Journal of Neuroinflammation 20 (1) , 245. 10.1186/s12974-023-02920-9

PDF - Published Version Available under License Creative Commons Attribution. Download (2MB)

Abstract

Background: Homozygous CD59-deficient patients manifest with recurrent peripheral neuropathy resembling Guillain-Barré syndrome (GBS), hemolytic anemia and recurrent strokes. Variable mutations in CD59 leading to loss of function have been described and, overall, 17/18 of patients with any mutation presented with recurrent GBS. Here we determine the localization and possible role of membrane-bound complement regulators, including CD59, in the peripheral nervous systems (PNS) of mice and humans. Methods: We examined the localization of membrane-bound complement regulators in the peripheral nerves of healthy humans and a CD59-deficient patient, as well as in wild-type (WT) and CD59a-deficient mice. Cross sections of teased sciatic nerves and myelinating dorsal root ganglia (DRG) neuron/Schwann cell cultures were examined by confocal and electron microscopy. Results: We demonstrate that CD59a-deficient mice display normal peripheral nerve morphology but develop myelin abnormalities in older age. They normally express myelin protein zero (P0), ankyrin G (AnkG), Caspr, dystroglycan, and neurofascin. Immunolabeling of WT nerves using antibodies to CD59 and myelin basic protein (MBP), P0, and AnkG revealed that CD59 was localized along the internode but was absent from the nodes of Ranvier. CD59 was also detected in blood vessels within the nerve. Finally, we show that the nodes of Ranvier lack other complement-membrane regulatory proteins, including CD46, CD55, CD35, and CR1-related gene-y (Crry), rendering this area highly exposed to complement attack. Conclusion: The Nodes of Ranvier lack CD59 and are hence not protected from complement terminal attack. The myelin unit in human PNS is protected by CD59 and CD55, but not by CD46 or CD35. This renders the nodes and myelin in the PNS vulnerable to complement attack and demyelination in autoinflammatory Guillain-Barré syndrome, as seen in CD59 deficiency.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	BioMed Central
ISSN:	1742-2094
Date of First Compliant Deposit:	25 October 2023
Date of Acceptance:	2 October 2023
Last Modified:	25 Oct 2023 09:15
URI:	https://orca.cardiff.ac.uk/id/eprint/163494

Actions (repository staff only)

Edit Item